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- Title
DLL4 regulates NOTCH signaling and growth of T acute lymphoblastic leukemia cells in NOD/SCID mice.
- Authors
Minuzzo, Sonia; Agnusdei, Valentina; Pusceddu, Irene; Pinazza, Marica; Moserle, Lidia; Masiero, Massimo; Rossi, Elisabetta; Crescenzi, Marika; Hoey, Timothy; Ponzoni, Maurilio; Amadori, Alberto; Indraccolo, Stefano
- Abstract
DLL4 blockade reduced NOTCH signaling and delayed growth of T-ALL cells in mice, by increasing their apoptosis. These effects are possibly mediated by a combination of direct effects on NOTCH signaling and indirect effects on the tumor microenvironment.Activation of the NOTCH pathway occurs commonly in T acute lymphoblastic leukemia (T-ALL) mainly due to mutations in NOTCH1 or alterations in FBW7 and is involved in the regulation of cell proliferation and survival. Since mutations hit different domains of the receptor, they are predicted to heterogeneously perturb ligand-induced NOTCH1 activity. Moreover, T-ALL cells also co-express NOTCH3 receptors which could be triggered by different ligands. In this study, we aimed to investigate the role of DLL4 in the regulation of NOTCH signaling in T-ALL cells in the context of different types of NOTCH1 mutation or wild-type NOTCH receptor, as well as the effects of DLL4 neutralization on T-ALL engraftment in mice.We found that NOTCH signaling can be stimulated in T-ALL cells in vitro by either human or murine DLL4 with heterogeneous effects, according to NOTCH1/FBW7 mutation status, and that these effects can be blocked by antibodies neutralizing DLL4, NOTCH1 or NOTCH2/3. In vivo, DLL4 is expressed in the spleen and the bone marrow (BM) of NOD/SCID mice bearing T-ALL xenografts as well as the BM of T-ALL patients. Importantly, DLL4 blockade impaired growth of T-ALL cells in NOD/SCID mice and increased leukemia cell apoptosis. These results show that DLL4 is an important component of the tumor microenvironment which contributes to the early steps of T-ALL cell growth.
- Subjects
DROSOPHILA proteins; NOTCH genes; CELLULAR signal transduction; T cells; CELL growth; LYMPHOBLASTIC leukemia; LABORATORY mice
- Publication
Carcinogenesis, 2015, Vol 36, Issue 1, p115
- ISSN
0143-3334
- Publication type
Article
- DOI
10.1093/carcin/bgu223